All tissues are sensitive to hypoperfusion and the resulting lack of oxygen, ischemia. Prolonged ischemia will result in cellular damage. The magnitude of the injury and the potential for tissue rescue depends upon the degree and duration of the ischemia. With long ischemic periods, cellular death occurs (infarction) and under these conditions the injury is irreversible. On the other hand, dying cells or cells targeted for cell death may be rescued by drug treatment, if applied in a timely fashion.
Major ischemic events of therapeutic concern include, but are not limited to, heart attacks and stroke. In man, stroke accounts for 10% of all premature deaths, and of those that survive the insult, 50% are left severely disabled. Only a small fraction, 10%, of patients actually recover full function.
Over 1,500,000 Americans suffer from myocardial infarctions each year. About half of these do not survive to reach the hospital. However, with the acceptance of thrombolytic therapy such as streptokinase or tissue plasminogen activator (TPA), the one month survival rate for patients who do reach the hospital is as high as 93.6% (Werns, S. W. Textbook of Interventional Cardiology, ed. Topol, E. J. WB Saunders: 1994, pp142-153). By lysing the clot early in the course of infarct, ischemic muscle and tissue can be salvaged. However, reperfusion in and of itself leads to tissue damage.
Reperfusion injury may occur as a result of one or more of the following events: cellular acidosis leading to calcium overload; increased intracellular osmotic loads of catabolites leading to cell swelling; free radicals from neutrophils and other inflammatory cells.
Neutrophils are seen in reperfused myocardium shortly after reperfusion. Monocytes/macrophages appear within 24 to 48 hours. Neutrophil infiltration is three to five fold greater in reperfused myocardium than in ischemic myocardium, is initiated by adhesion to endothelial cells, and occurs within 10 minutes of reperfusion. Neutrophils in and of themselves may become trapped in capillaries and impede reperfusion. Intravascular neutrophils may block up to 27% of the capillaries, and have been shown to be related to decreased regional blood flow (Forman et al., Acute Myocardial Infarction, eds. Gersh et al. Elsevier: 1991, pp 347-370). This can result in the "no-reflow" phenomenon, where blood flow continues to decrease after reperfusion.
It is known that neutrophils must first adhere themselves to the endothelial cell wall through the interactions with adhesion molecules. Once attached to the vessel cell wall, the neutrophils then force themselves between adjacent endothelial cells and move into the brain tissue, where they release cytotoxic cytokines. The expression of such adhesion molecules is increased following cell damage including ischemia. In addition, endothelial cell walls become more permeable to infiltrating cells due to the release of nitric oxide (NO). Agents that inhibit the movement (diapedesis) of neutrophils from surrounding blood vessels into the damaged tissue may thus be of value in allowing dying cells time to recover from the ischemic insult.
There is a need in the art for effective therapies to prevent or reduce the consequences of ischemia.